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  • Review Article
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The outs and the ins of sphingosine-1-phosphate in immunity

Nature Reviews Immunology volume 11, pages 403–415 (2011)Cite this article

Subjects

Key Points

  • The bioactive lipid mediator sphingosine-1-phosphate (S1P) is produced by the sphingosine kinases SPHK1 and SPHK2, and has emerged as a crucial regulator of immunity. Erythrocytes and the lymphatic endothelium are the main contributors to the high levels of S1P in the plasma and lymph, respectively. Trafficking of immune cells relies on S1P receptors (S1PRs) to sense gradients of S1P within and between lymphoid tissues and the circulation. The expression of these receptors is tightly regulated temporally and spatially.

  • Recent studies using pharmacological and genetic approaches combined with intravital staining explain how S1PR1 regulates the egress of newly formed T cells from the thymus and the exit of mature T and B cells from secondary lymphoid organs.

  • Plasma S1P maintains vascular integrity. S1PRs have distinct roles in inflammation-induced vascular permeability. S1P ligation of S1PR1 on endothelial cells induces RAC-dependent adherens junction assembly to enhance barrier integrity, whereas S1PR2 and S1PR3 promote vascular permeability through activation of a RHO-dependent pathway.

  • Many environmental cues, including cytokines and growth factors, stimulate SPHK1 to produce S1P, which is then exported out of cells by specific transporters to activate S1P receptors on the same cell or neighbouring cells. This process, called S1P inside-out signalling, regulates many processes that are important for immunity and inflammation.

  • It has long been suspected that S1P has direct intracellular actions independent of its receptors. Recent studies have uncovered intriguing intracellular targets relevant to immunology, including TNF receptor-associated factor 2 (TRAF2), protein kinase Cδ (PKCδ) and histone deacetylases (HDACs).

  • S1P binds to TRAF2, a key component in the nuclear factor-κB (NF-κB) signalling pathway that is triggered by tumour necrosis factor (TNF), and stimulates its E3 ubiquitin ligase activity. This suggests a novel paradigm for the regulation of K63-linked polyubiquitylation and provides a mechanistic explanation for the numerous observations of the importance of SPHK1 in inflammatory, anti-apoptotic and immune processes.

  • Sepsis is an overwhelming multi-organ immune response to bacterial infections. Toll-like receptor 4 (TLR4) is a sensor of lipopolysaccharide (LPS), a component of bacterial cell walls. Signalling from TLR4 leads to the activation of SPHK1 and the production of S1P, which has important roles in sepsis-induced inflammatory responses. The SPHK1–S1P–S1PR3 axis downstream of protease-activated receptor 1 (PAR1) signalling in dendritic cells regulates late-phase amplification of inflammation during sepsis. In macrophages, S1P produced by SPHK1 stimulates PKCδ, leading to the activation of the IκB kinase (IKK) complex and NF-κB in response to LPS and bacterial lipoprotein.

  • Histone deacetylases (HDACs) remove acetyl groups from the N-terminal tails of histones, and this represses gene transcription. S1P produced in the nucleus by SPHK2, which is present together with HDACs in repressor complexes, binds to and inhibits HDACs, allowing transcription of specific genes to occur.

  • Preclinical and clinical studies suggest that diverse pharmacological agents that target the functions of S1P and its receptors have therapeutic potential for treating a wide range of inflammatory and autoimmune disorders. The sphingosine analogue FTY720 (fingolomod) is the first orally effective therapeutic for the treatment of multiple sclerosis.

Abstract

The potent lipid mediator sphingosine-1-phosphate (S1P) is produced inside cells by two closely related kinases, sphingosine kinase 1 (SPHK1) and SPHK2, and has emerged as a crucial regulator of immunity. Many of the actions of S1P in innate and adaptive immunity are mediated by its binding to five G protein-coupled receptors, designated S1PR1–5, but recent findings have also identified important roles for S1P as a second messenger during inflammation. In this Review, we discuss recent advances in our understanding of the roles of S1P receptors and describe the newly identified intracellular targets of S1P that are crucial for immune responses. Finally, we discuss the therapeutic potential of new drugs that target S1P signalling and functions.

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Figure 1: A simplified scheme of S1P synthesis and metabolism and inside-out signalling.
Figure 2: Regulation of T cell egress by S1PR1.
Figure 3: FHL2-mediated repression of S1pr1 expression and regulation of DC migration.
Figure 4: The dual role of PAR1 and inside-out signalling by S1P in the regulation of endothelial barrier function.
Figure 5: Roles of S1P produced by SPHK1 in TNFR signalling.
Figure 6: Roles of S1P produced by SPHK1 in TLR4 signalling.
Figure 7: S1P produced by SPHK2 in the nucleus inhibits HDACs and regulates gene transcription.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (to S.S.).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, 23298, Virginia, USA

    Sarah Spiegel & Sheldon Milstien

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  1. Sarah Spiegel
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  2. Sheldon Milstien
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Correspondence to Sarah Spiegel.

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Glossary

S1P receptors

A family of five G protein-coupled receptors. The binding of sphingosine-1-phosphate (S1P) to these receptors activates heterotrimeric GTP-binding proteins, leading to the activation of downstream signalling.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of cell surface receptors. By contrast, outside-in signalling is the process by which ligation of a cell surface receptor activates signalling pathways inside the cell.

Transitional B cells

Transitional B cells are short-lived immature B cells that either die or are selected into the peripheral mature B cell repertoire. Transitional B cells can be subdivided into three subsets (T1, T2 and T3 cells) based on differential phenotypical and functional characteristics.

Reverse transmigration

Migration of cells across the endothelial basement membrane and, subsequently, across the endothelial barrier.

Marginal zone bridging channels

Structures in the spleen that are thought to allow the passage of lymphocytes from the red pulp to the white pulp.

Anaphylaxis

A severe whole body allergic reaction that is life threatening.

E3 ubiquitin ligases

Enzymes that attach the molecular tag ubiquitin to proteins. Depending on the number of ubiquitin molecules that are attached and the positioning of the links between them, the ubiquitin tag can target proteins for degradation by the proteasome, sort them to specific subcellular compartments or modify their biological activity.

Sepsis

A potentially serious medical condition that involves a whole-body inflammatory response to an infection.

FTY720

A sphingosine-like drug that is phosphorylated intracellularly by sphingosine kinase. Phosphorylated FTY720 is an agonist of all of the sphingosine-1-phosphate receptors (S1PRs) except S1PR2, but its immunosuppressive functions are due to prolonged downregulation and degradation of S1PR1.

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Spiegel, S., Milstien, S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11, 403–415 (2011). https://doi.org/10.1038/nri2974

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